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Immunology > Human Leukocyte Antigens > Flashcards

Human Leukocyte Antigens Flashcards

1
Q

MHC represent _% of the genome

A

.1

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2
Q

What chromosome and arm is MHC on

A

Chromosome 6, short arm

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3
Q

The MHC contains a group of genes that encode what

A

Human leukocyte antigens HLA

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4
Q

Difference between MHC and HLA

A

MHC-collection of genes

HLA-human MHC

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5
Q

The T cell only recognizes antigens in the groove of an ____ molecule

A

HLA

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6
Q

Are differences in HLA responsible for organ and tissue rejection after transplantation

A

Yup

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7
Q

Some HLA genes are related to disease

A

Type 1 diabetes, MS, ankylosis spondylitis

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8
Q

HaplotypE

A

Collection of genes inherited as a whole group

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9
Q

Gene polymorphism

A

Availability in the gene pool of the population of many different allelic forms of a gene at a particular locus

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10
Q

Linkage disequilibrium

A

Alleles appearing together not he same haplotype more frequently. Than their single gene frequencies suggest;implies that meiosis recombination is non random

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11
Q

B27

A

Ankylosing spondylitis

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12
Q

MHC restriction

A

Antigen specific cytotoxic T cell responses are restricted ot kill only those target cells that bear the correct MHC molecule

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13
Q

What is in the human HLA/MHC

A

Three major classes, I, II, III, gene for 21 hydroxylase, TNFa, heat shock protein 70

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14
Q

Class I MHC

A

Furthest from centromere
HLA-A, B, C
Present peptide antigens to T cells

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15
Q

Why are MHC1 classical

A

Present peptide antigens to T cells

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16
Q

What do class 1 genes encode

A

A chains B chains

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17
Q

The class B chain joins the class a chain to create what

A

B2-microglobulin

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18
Q

Chat chromosome is the gene for B2 microglobulin on

A

15

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19
Q

Unlink the _ chain, the genes encoding the _ chains vary. The number of alleles can be considerable, it is called __ ___

A

B a gene polymorphism

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20
Q

How do we identify different HLA genes

A

HLA typing

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21
Q

What are non classical HLA class 1 genes

A

Ib less polymorphic , more restricted expression on specialized cell types and present a restricted type of peptide or none at all

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22
Q

What are the main genes of class Ib non classical HLA class I

A

HLA-A, F, G

*some have interactions with NK cells

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23
Q

MIC genes

A 
Class Ic 
Genes lie between class I and III 
Code proteins with similar overall structure to class I , but do not bind peptide antigen to present to T cell
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24
Q

What are the two MHC class 1 related (MIC or class IC) genes

A

A and B

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25
Q

Are MIC polymorphic

A

Highly

MICA and MICB have over 70 alleles

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26
Q

Where are MIC genes expressed

A

Epithelial surface and participate in an interaction with lymphocytes that signals cellular stress

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27
Q

What are the three major subregions of class II HLA

A

DP, DQ, DR

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28
Q

What do DP, DQ, DR encode

A

Molecules that present antigen to T cells

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29
Q

What else is encoded in class II

A

HLA-DM, DO, TAP, PSMB

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30
Q

Two distinct polypeptide chains, _ and _ chains combine to form class II HLA DR, DQ, DP

A

A b

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31
Q

Class I and II are ____ bc they are made up of two different chains

A

Heterodimer

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32
Q

Why do all HLA-DR molecules have the same a chain

A

DR subregion contains only a single a chain gene (DRA

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33
Q

The number of DRB genes expressed in an individual depends on the ____

A

HaplotypE

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34
Q

DRA has _ allelic forms

A

No

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35
Q

The a chain is ___

A

Invariant

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36
Q

The DRB genes are highly ___

A

Variable

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37
Q

Like class I region, DRB is highly ____

A

Polymorphic

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38
Q

Since only the ___ genes are polymorphic, it is these that determine the particular HLA-DR type

A

DRB

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39
Q

In the DQ region, both DQA1 and DQAb are _____

A

Polymorphic

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40
Q

Int he DP region, DPA1 and DPB1 encode a and b chains. Are they polymorphic?

A

DP a chain low polymorphism DP b is highly polymorphic

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41
Q

DM—-DMA and DMB

A

Ab heterodiner
Rarely expressed on cell surface
Play role in loading peptide into the other “more conventional” class II HLA molecules

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42
Q

DO

A

HLA-DO

Role in regulating the antigen loading process

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43
Q

PSMB8 and 9 also in class II region

A

Code for proteosome subunit beta type 8 and 9

Proteins in the proteosome 
Cleave proteins into smaller peptides for binding to class I HLA
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44
Q

TAP1 TAP2

A

Encode one half of a peptide transporter responsible for transporting peptides of the required length into the class I synthesis compartment for loading

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45
Q

Class III region

A

Between classs I and II

Several genes coding for complement components

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46
Q

What are the three classes of HLA

A

I, II and III

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47
Q

What do class I and II encode

A

Proteins that physically present peptide antigens to T lymphocytes

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48
Q

What do class III HLA encode

A

Complement proteins

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49
Q

__ ___ in class I and II regions ensured that at a population level there are many different versions of clas I and II genes

A

Gene polymorphism

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50
Q

Each of us possess a discrete number of different class I and II genes

A

Ok

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51
Q

Two complementary chromosome strands, one maternal and one paternal are inherited each strand providing an MHC _____

A

Haplotype

52
Q

What kind of expression do MHC have and what does this mean

A

Co-dominance

Both maternally and paternally derived allelic forms are expressed as cell surface proteins

53
Q

HaplotypE encoding class II HLA are inherited in a similar fashion. Except what

A

HaplotypE int his region do not necessarily contain a full complement of DRB loci. However all HaplotypE contain the DRB1 locus which is the location of the best studies HLA-DR genes

54
Q

What two things are special about MHC inheritance (although Mendelian)

A

Polymorphism

Linkage disequilibrium

55
Q

Linkage disequilibrium

A

Certain alleles are found together on the Same haplotype with greater frequency than should occur if recombination during meiosis was random

56
Q

Extended HaplotypE

A

Long segments of chromosome that incorporate genes from all three MHC classes and are passes on undisturbed from generation to generation

57
Q

HLA typing

A

For transplantation

Amplify with pcr

58
Q

What cells are class 1 molecules on

A

All cells except erythrocytes and trophoblasts

59
Q

What are class II cells on

A 
Macrophages 
Monocytes
Dendritic cells 
B cells 
Not plasma cells
60
Q

What are the antigen presenting cells

A

Macrophages and monocytes
Dendritic cells
B cells

61
Q

Under the influence of cytokines during inflammation (interferons-a and y, TNF) a whole range of cells that typically only express MHC I may be induced to express ______ and _____ the number of MHCI…important for what

A

MHCII
Unregulated
Eradicate intracellular viral infections

62
Q

Each of us expresses on the cell surface both maternally and paternally derived HLA molecules ; the genes are inherited in large chunks called ____

A

HaplotypE

63
Q

Structure of class I molecule

A

HLAA, B, C are formed from polymorphic heavy chain glycoproteins that bind non covalently to the B chain, B2 microglobulin

64
Q

Class II structure

A

HLA-DP, DQ, DR are formed from two glycoproteins , an a chain and a B chain

65
Q

Describe binding of T cell to antigen and MHCI

A

T cell receptor encounters a deep grooved binding site, 2.5 no long, 1 no wide and 1 no deep, closed at either end and occupied by an antigenic peptide of around 9 aa residues in length . This groove is fashioned by 1 a helices which made up the sides, on top of a floor comprising eithe antiparalell b pleated sheets. The a helices and floor contain holes that can accomodate side chains poling out from the different aa in the bound peptide

66
Q

What accounts for the difference between variations like A2 and A68

A

Polypeptide backbone very similar
Difference from nature of aa in position lining flow and sides of the groove
Sidechains of the pockets influence
Small differences in HLA can eve profound

67
Q

Population level differences are ___

A

Polymorphism

68
Q

Individual level differences are

A

Can express several different class I molecules by having multiple loci and co dominance increase Arnce of antigenic peptides

69
Q

What is different about MHCII from MHCI

A

Peptide binding groove is larger and is not closed at either end allowing the peptide to protrude

Makes sense bc peptides are almost double the length on MHCII than MHCI

70
Q

The source of a peptide dictates what

A

Wherther is it bound to MHCI or II

71
Q

Antigens are degraded inside cells and the ___ are bound to HLA

A

Peptides

72
Q

What peptides are bound to MHCI

A

Peptides derived from proteins synthesized endogenously within the cell presenting the antigen

73
Q

MHCI can display __ proteins. Why

A

Viral

During a viral infection, viral proteins are synthesized endogenously using the host cells machinery.

74
Q

What peptides are bound to MHCII

A

Peptides derived from outside cell (exogenous antigens) are taken into cell, processed using proteolytic enzymes and presented

75
Q

What use the endogenous pathway what uses the exogenous pathway

A

Endogenous I

Exogenous II

76
Q

What types of peptides are on MHCII

A

Plasma proteins

This changes during infection

77
Q

MHC restriction

A

Only T cells bearing a surface glycoproteins molecule that binds to a fixed non varying point on the clas II B chain, are able to interact with clas II presented peptides

78
Q

What is the function of CD4 and CD8 accessory molecules

A

Stabilize interaction fo T cell receptor and hla molecule-peptide compels

79
Q

From a class I MHC, the eluded peptides are typically _ aa longand composed of endogenous proteins

A

9

80
Q

What kind of forces fit the aa into MHCI

A

Non covalent
H bonding and van dear walls and electrostatic forces
Each sidechain slides into the pockets, labeled 1-9

81
Q

What are the major anchoring pockets

A

P2 P9

82
Q

Therefore, the P2 and P9 position pockets are ___

A

Constant

83
Q

Motif

A

The characteristic sequence of a peptide for a particular HLA molecule

84
Q

Why may the middle region of the peptide bulge out of MHCI

A 
May be forced to bend to fit in class I
This bulging part is what T cell interacts with
85
Q

The binding of peptide to a class I molecules is __ than to a class II molecule

A

Tighther

86
Q

Since binding to class I is stronger it can be considered ___

A

Irreversible

87
Q

Half life of MHC complex on cell

A

30 hours

88
Q

What is the dissociation constant

A

Ration between the rate at which molecules associate and dissociate

89
Q

Antigen and antibody associate ___ and dissociate —-

A

Faster slower

90
Q

What is the kinetics of the molecule peptide interaction

A

10^-5 to 10^-6, slow association and very slow dissociation

91
Q

What is the major difference in MHCII

A

Longer peptide
Groove is open at each end so peptide hangs out at each side(no bulge)

Looser fit for peptides

92
Q

With no infection what is in MHCII. What about with infection

A

Plasma membrane associated proteins and others…

Bacteria

93
Q

Describe exogenous pathway

A

Proteins internalized into the endosomal and lysosomal compartments, where clas II HLA molecules are loaded….if bacterium internazlied at same time, peptide fragments fromt his pathogen willl also be presented

94
Q

The peptides found in class II HLA are how many aa long

A

13-18

95
Q

The pockets for interaction between peptide and class II groove are -

A

P1-P9 also

96
Q

What are the major,

A

P1, P4, P6, P9

97
Q

Different HLA molecules have different have different structural features in these pockets bc of ____

A

Polymorphism

98
Q

Peptide binding motif

A

HLAII molecules can be characterized as this

99
Q

Class II peptides display ____, in other words the same peptide may bind to several different types of class II molecules

A

Promiscuity

100
Q

Class I genetic organization

A

Polymorphic a chain genes in MHC (on chromosome 6 in humans)

Monomorphic B chain gene (on chromosome in 15 in humans )

101
Q

Class II molecules genetic organization

A

Polymorphic a and B chain genes in MHC (on chromosome 6 in humans)

102
Q

Class I molecule molecular structure

A

Non-covalently associated ab dimer

103
Q

Class II molecular structure

A

Non-covalently associated ab dimer

104
Q

Class I binding groove

A

Two a helices flanking a floor of B pleated sheets

105
Q

Class II binding groove

A

Two a helices flanking a floor of B pleated sheets

106
Q

Peptide size class I

A

8-10 aa

107
Q

Class II peptide size

A

10-34usuually 15

108
Q

Class I peptide source

A

Endogenous proteins (including virus infected cells

109
Q

Class II molecules peptide source

A

Exogenous and endogenous proteins derived from endosomal compartments situated near plasma membrane

110
Q

Class I cellular site of peptide binding

A

Early-during assembly of class I molecule

Peptide required for correct folding of dimer

111
Q

Class II cellular site of peptide binding

A

Late:in a specialized endosome

Invariant chain(but not peptide) required for folding of dimer

112
Q

Class I affinity of peptide

A

High

113
Q

Class II affinity for peptide

A

Moderate

114
Q

What is polymorphism

A

Numerous different alleles can occur at a single locus

115
Q

Since MHC co-dominant, do heterozygous or homozygous have the advantage

A

Heterozygous can make more combinations

116
Q

Can a groove of MHC accomodate all peptides

A

No, but a range

117
Q

Polymorphism has 2 important consequences for an individual what are they.

A

Unrelated individuals have a diverse susceptibility to disease and also promptly reject organ transplants between each other

118
Q

The extended HaplotypE HLA-A *0101, HLA-B *0801, HLA-DRB! *0301 and complement C4AQO

A

Present on a dingle chromosome together and occur in patients with a range of diseases that under the umbrella term “inflammatory or autoimmune “
Vascultis or diabetes
Common in Caucasian’s enhanced survivial from a viral or bacterial epidemic afflicting Northern Europe millenia ago

*aggressive hyperresponsiveness may leave individuals prone to developing inappropriate immune responses giving a greater tendency towards chronic inflammatory conditions and responses to self antigens

119
Q

Where do variable regions responsible for polymorphism generally lie

A

Along a helices that form margin of groove and B pleated sheets where the pockets are

120
Q

How does TCR interact with the complex

A

TCR straddles the peptide binding groove of HLA at an angle of 45 degrees

121
Q

Why tcr bind at 45 degrees

A

Two hypervariable regions (CDR1 and CDR2 of the a chain) bind one a helix whilst two other hypervariable regions (CDR1 and CDR2 of the b chain) bind the other a helix of the HLA molecule

122
Q

What regions of the TCR are the only parts to interact with the peptide

A

CDR3 regions of a and b chains

123
Q

Can TCR bind to different peptides yea if has center of the groove contains the same of similar aa

A

One tcr can recodgnize more than one peptide

124
Q 
Nomenclature for class 1
Example: HLA-A*0101
A

A is thee allel
Asterisk then two digit number defining HLA type
Then two digitr for the variants of that type

125
Q 
Nomenclature class II example 
HLA-DRB1*0101
A

Letters defining locus followed by A or B for A or B chain
Number defining locus if more than 1 exists
First two letters for types
Second two letters for variants

Immunology (14 decks)

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